Topical exposure to pesticides is a primary route of entry for systemic toxicity in humans. The purpose of this proposal is to continue to employ the isolated perfused porcine skin flap (IPPSF) as a biologically relevant in vitro model to quantitate pesticide absorption and cutaneous distribution after topical application. This model system is ideally suited to study these phenomenon because it is an isolated perfused tissue model which has an intact and viable epidermis in association with a functional microcirculation. Previous studies have shown its ability to estimate in vivo absorption in humans for a variety of compounds and to detect the direct cutaneous toxicity of these same compounds. By utilizing a physiologically-relevant pharmacokinetic model, the relationships of pesticide penetration through the skin, distribution within the skin and absorption into the circulation can be quantitatively studied. The effects of cutaneous biotransformation can also be integrated into this model. In order to correlate IPPSF model parameters with physical and chemical properties of topical pesticides, additional compounds from different chemical classes are required. This will allow for the definition of structure-activity relationships to be made which govern penetration and absorption in a biologically complex in vitro system. The objective of the present project is to model the penetration, distribution, absorption, and direct cutaneous toxicity of ten pesticides from three chemical classes which are being studied in other program projects. Three doses of each compound will be modelled as will the effects of occlusive and nonocclusive applications. By the end of this project, these data should improve the basis upon which rational toxicologic assessments can be made for topically applied pesticides.